title: Comparison of the activity of three different HSP70 inhibitors on apoptosis, cell cycle arrest, autophagy inhibition, and HSP90 inhibition.
abstract: The chaperone HSP70 promotes the survival of cells exposed to many different types of stresses, and is also potently anti-apoptotic. The major stress-induced form of this protein, HSP70-1, is overexpressed in a number of human cancers, yet is negligibly expressed in normal cells. Silencing of the gene encoding HSP70-1 (HSPA1A) is cytotoxic to transformed but not normal cells. Therefore, HSP70 is considered to be a promising cancer drug target, and there has been active interest in the identification and characterization of HSP70 inhibitors for cancer therapy. Because HSP70 behaves in a relatively non-specific manner in the control of protein folding, to date there are no reliably-identified "clients" of this protein, nor is there consensus as to what the phenotypic effects of HSP70 inhibitors are on a cancer cell. Here for the first time we compare three recently-identified HSP70 inhibitors, PES-Cl, MKT-077, and Ver-155008, for their ability to impact some of the known and reported functions of this chaperone; specifically, the ability to inhibit autophagy, to influence the level of HSP90 client proteins, to induce cell cycle arrest, and to inhibit the enzymatic activity of the anaphase-promoting complex/cyclosome (APC/C). We report that all three of these compounds can inhibit autophagy and cause reduced levels of HSP90 client proteins; however, only PES-Cl can inhibit the APC/C and induce G 2/M arrest. Possible reasons for these differences, and the implications for the further development of these prototype compounds as anti-cancer agents, are discussed.
authors.affiliation: Program in Molecular and Cellular Oncogenesis; The Wistar Institute; Philadelphia PA USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Budina-Kolomets
authors.affiliation: Program in Molecular and Cellular Oncogenesis; The Wistar Institute; Philadelphia PA USA.
authors.forename: Gregor M
authors.initials: GM
authors.lastname: Balaburski
authors.affiliation: Program in Molecular and Cellular Oncogenesis; The Wistar Institute; Philadelphia PA USA.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Bondar
authors.affiliation: Institute for Cancer Research; Fox Chase Cancer Center; Philadelphia PA USA.
authors.forename: Neil
authors.initials: N
authors.lastname: Beeharry
authors.affiliation: Institute for Cancer Research; Fox Chase Cancer Center; Philadelphia PA USA.
authors.forename: Tim
authors.initials: T
authors.lastname: Yen
authors.affiliation: Program in Molecular and Cellular Oncogenesis; The Wistar Institute; Philadelphia PA USA.
authors.forename: Maureen E
authors.initials: ME
authors.lastname: Murphy
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D045744:Cell Line, Tumor; D018840:HSP70 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D011684:Purine Nucleosides / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology
chemical_list: C545747:2-phenylacetylenesulfonamide; C553334:AMBRA1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D018840:HSP70 Heat-Shock Proteins; D011684:Purine Nucleosides; D011725:Pyridines; D013449:Sulfonamides; D013844:Thiazoles; C550733:VER 155008; C097880:MKT 077
keywords: MKT-077; PES; PES-Cl; Ver-155008; anaphase promoting complex; autophagy; cell cycle; phenylethynesulfonamide